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A C-terminal ataxin-2 disordered region promotes Huntingtin protein aggregation and neurodegeneration in Drosophila models of Huntington’s disease

The Ataxin-2 (Atx2) protein contributes to the progression of neurodegenerative phenotypes in animal models of amyotrophic lateral sclerosis (ALS), type 2 spinocerebellar ataxia (SCA-2), Parkinson’s disease, and Huntington’s disease (HD). However, because the Atx2 protein contains multiple separable...

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Autores principales: Huelsmeier, Joern, Walker, Emily, Bakthavachalu, Baskar, Ramaswami, Mani
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8664476/
https://www.ncbi.nlm.nih.gov/pubmed/34718534
http://dx.doi.org/10.1093/g3journal/jkab355
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author Huelsmeier, Joern
Walker, Emily
Bakthavachalu, Baskar
Ramaswami, Mani
author_facet Huelsmeier, Joern
Walker, Emily
Bakthavachalu, Baskar
Ramaswami, Mani
author_sort Huelsmeier, Joern
collection PubMed
description The Ataxin-2 (Atx2) protein contributes to the progression of neurodegenerative phenotypes in animal models of amyotrophic lateral sclerosis (ALS), type 2 spinocerebellar ataxia (SCA-2), Parkinson’s disease, and Huntington’s disease (HD). However, because the Atx2 protein contains multiple separable activities, deeper understanding requires experiments to address the exact mechanisms by which Atx2 modulates neurodegeneration (ND) progression. Recent work on two ALS models, C9ORF72 and FUS, in Drosophila has shown that a C-terminal intrinsically disordered region (cIDR) of Atx2 protein, required for assembly of ribonucleoprotein (RNP) granules, is essential for the progression of neurodegenerative phenotypes as well as for accumulation of protein inclusions associated with these ALS models. Here, we show that the Atx2-cIDR also similarly contributes to the progression of degenerative phenotypes and accumulation of Huntingtin protein aggregates in Drosophila models of HD. Because Huntingtin is not an established component of RNP granules, these observations support a recently hypothesized, unexpected protein-handling function for RNP granules, which could contribute to the progression of Huntington’s disease and, potentially, other proteinopathies.
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spelling pubmed-86644762021-12-13 A C-terminal ataxin-2 disordered region promotes Huntingtin protein aggregation and neurodegeneration in Drosophila models of Huntington’s disease Huelsmeier, Joern Walker, Emily Bakthavachalu, Baskar Ramaswami, Mani G3 (Bethesda) Investigation The Ataxin-2 (Atx2) protein contributes to the progression of neurodegenerative phenotypes in animal models of amyotrophic lateral sclerosis (ALS), type 2 spinocerebellar ataxia (SCA-2), Parkinson’s disease, and Huntington’s disease (HD). However, because the Atx2 protein contains multiple separable activities, deeper understanding requires experiments to address the exact mechanisms by which Atx2 modulates neurodegeneration (ND) progression. Recent work on two ALS models, C9ORF72 and FUS, in Drosophila has shown that a C-terminal intrinsically disordered region (cIDR) of Atx2 protein, required for assembly of ribonucleoprotein (RNP) granules, is essential for the progression of neurodegenerative phenotypes as well as for accumulation of protein inclusions associated with these ALS models. Here, we show that the Atx2-cIDR also similarly contributes to the progression of degenerative phenotypes and accumulation of Huntingtin protein aggregates in Drosophila models of HD. Because Huntingtin is not an established component of RNP granules, these observations support a recently hypothesized, unexpected protein-handling function for RNP granules, which could contribute to the progression of Huntington’s disease and, potentially, other proteinopathies. Oxford University Press 2021-10-09 /pmc/articles/PMC8664476/ /pubmed/34718534 http://dx.doi.org/10.1093/g3journal/jkab355 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Investigation
Huelsmeier, Joern
Walker, Emily
Bakthavachalu, Baskar
Ramaswami, Mani
A C-terminal ataxin-2 disordered region promotes Huntingtin protein aggregation and neurodegeneration in Drosophila models of Huntington’s disease
title A C-terminal ataxin-2 disordered region promotes Huntingtin protein aggregation and neurodegeneration in Drosophila models of Huntington’s disease
title_full A C-terminal ataxin-2 disordered region promotes Huntingtin protein aggregation and neurodegeneration in Drosophila models of Huntington’s disease
title_fullStr A C-terminal ataxin-2 disordered region promotes Huntingtin protein aggregation and neurodegeneration in Drosophila models of Huntington’s disease
title_full_unstemmed A C-terminal ataxin-2 disordered region promotes Huntingtin protein aggregation and neurodegeneration in Drosophila models of Huntington’s disease
title_short A C-terminal ataxin-2 disordered region promotes Huntingtin protein aggregation and neurodegeneration in Drosophila models of Huntington’s disease
title_sort c-terminal ataxin-2 disordered region promotes huntingtin protein aggregation and neurodegeneration in drosophila models of huntington’s disease
topic Investigation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8664476/
https://www.ncbi.nlm.nih.gov/pubmed/34718534
http://dx.doi.org/10.1093/g3journal/jkab355
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